Nuclear receptor Rev-erbα alleviates intervertebral disc degeneration by recruiting NCoR–HDAC3 co-repressor and inhibiting NLRP3 inflammasome

Abstract

Intervertebral discs (IVDs) are rhythmic tissues that experience daily low-load recovery. Notably, aging and abnormal mechanical stress predispose IVDs to degeneration due to dysrhythmia-induced disordered metabolism. Meanwhile, Rev-erbα acts as a transcriptional repressor in maintaining biorhythms and homeostasis; however, its function in IVD homeostasis and degeneration remains unclear. This study assessed the relationship between low Rev-erbα expression levels and IVD degeneration. Rev-erbα deficiency accelerated needle puncture or aging-induced IVD degeneration, characterized by increased extracellular matrix (ECM) catabolism and nucleus pulposus (NP) cell apoptosis. Mechanistically, Rev-erbα knockdown in NP cells aggravated rhIL1β-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, exacerbating the imbalanced ECM and NP cell apoptosis. Meanwhile, blocking NLRP3 inflammasome activation mitigated Rev-erbα deficiency and needle puncture-induced IVD degeneration. Particularly, Rev-erbα mediated the transcriptional repression of the NLRP3 inflammasome via the ligand heme-binding of nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3) complex. Thus, the increased expression of Rev-erbα in NP cells following short-term rhIL1β treatment failed to inhibit NLRP3 transcription in vitro owing to heme depletion. Pharmacological activation of Rev-erbα in vivo and in vitro alleviated IVD degeneration by altering the NLRP3 inflammasome. Taken together, targeting Rev-erbα may be a potential therapeutic strategy for alleviating IVD degeneration and its related diseases.

References

[1] MorrisH, Gonçalves CF, DudekM, HoylandJ, MengQ. Tissue physiology revolving around the clock: circadian rhythms as exemplified by the intervertebral disc. Ann Rheum Dis. 2021; 80:828-839.

[2] RisbudMV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014; 10:44-56.

[3] ZehraU, Tryfonidou M, IatridisJC, Illien-JüngerS, Mwale F, SamartzisD. Mechanisms and clinical implications of intervertebral disc calcification. Nat Rev Rheumatol. 2022; 18:352-362.

[4] RobertsS, EvansH, TrivediJ, Menage J. Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am. 2006; 88:10-14.

[5] WuJ, ChenY, LiaoZ, et al. Self-amplifying loop of NF-kB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration. Mol Ther. 2022; 30:3241-3256.

[6] VergroesenPPA, KingmaI, EmanuelKS, et al. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr Cartil. 2015; 23:1057-1070.

[7] DudekM, YangN, RuckshanthiJP, et al. The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration. Ann Rheum Dis. 2017; 76:576-584.

[8] WangD, PengP, DudekM, et al. Restoring the dampened expression of the core clock molecule BMAL1 protects against compression-induced intervertebral disc degeneration. Bone Res. 2022; 10:20-32.

[9] PourcetB, Zecchin M, FerriL, et al. Nuclear receptor subfamily 1 group D member 1 regulates circadian activity of NLRP3 Inflammasome to reduce the severity of fulminant hepatitis in mice. Gastroenterology. 2018; 154:1449-1464.e20.

[10] WangS, LinY, YuanX, Li F, GuoL, WuB. REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis. Nat Commun. 2018; 9:4246.

[11] AkagiR, AkatsuY, FischKM, et al. Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-β signaling in chondrocytes. Osteoarthr Cartil. 2017; 25:943-951.

[12] ReppertSM, WeaverDR. Coordination of circadian timing in mammals. Nature. 2002; 418:935-941.

[13] PandaS, Hogenesch JB, KaySA. Circadian rhythms from flies to human. Nature. 2002; 417:329-335.

[14] DingSL, ZhangTW, ZhangQC, et al. Excessive mechanical strain accelerates intervertebral disc degeneration by disrupting intrinsic circadian rhythm. Exp Mol Med. 2021; 54:1911-1923.

[15] ChenW, ZhengD, ChenH, et al. Circadian clock regulation via biomaterials for nucleus pulposus. Adv Mater. 2023; 35:e2301037.

[16] WangS, LiF, LinY, WuB. Targeting REV-ERBα for therapeutic purposes: promises and challenges. Theranostics. 2020; 10:4168-4182.

[17] KimYH, MarhonSA, ZhangY, Steger DJ, WonK, LazarMA. Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription. Science. 2018; 359:1274-1277.

[18] KojetinDJ, BurrisTP. REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov. 2014; 13:197-216.

[19] QianZ, LiuZ, FengZ, Cai Z, QiuY, ZhuZ. Blocking circadian clock factor rev-erbα inhibits growth plate chondrogenesis via up-regulating MAPK-ERK1/2 pathway. Cell Cycle. 2023; 22:73-84.

[20] YinL, WuN, CurtinJC, et al. Rev-erbα a Heme sensor that coordinates metabolic and circadian pathways. Science. 2007; 318:1786-1789.

[21] SoltLA, WangY, BanerjeeS, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012; 485:62-68.

[22] YinL, WuN, LazarMA. Nuclear receptor rev-Erbα: a Heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal. 2010; 8:e001.

[23] RaghuramS, Stayrook KR, HuangP, et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ. Nat Struct Mol Biol. 2007; 14:1207-1213.

[24] ChenS, WuX, LaiY, et al. Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc. Bone Res. 2022; 10:1-13.

[25] JiM, JiangH, ZhangX, et al. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat Commun. 2018; 9:5051-5064.

[26] BenoistM. Natural history of the aging spine. Eur Spine J. 2003; 12: S86-S89.

[27] LiangC, KeQ, LiuZ, et al. BMAL1 moonlighting as a gatekeeper for LINE1 repression and cellular senescence in primates. Nucleic Acids Res. 2022; 50:3323-3347.

[28] PariollaudM, GibbsJE, HopwoodTW, et al. Circadian clock component REV-ERBá controls homeostatic regulation of pulmonary inflammation. J Clin Invest. 2018; 128:2281-2296.

[29] CurtisAM, BelletMM, Sassone-CorsiP, O’NeillLA. Circadian clock proteins and immunity. Immunity. 2014; 40:178-186.

[30] BenitahSA, WelzPS. Circadian regulation of adult stem cell homeostasis and aging. Cell Stem Cell. 2020; 26:817-831.

[31] Acosta-RodríguezVA, Rijo-FerreiraF, GreenCB, TakahashiJS. Importance of circadian timing for aging and longevity. Nat Commun. 2021; 12:2862-2873.

[32] QianZ, ZhangY, KangX, et al. Postnatal conditional deletion of Bmal1 in osteoblasts enhances trabecular bone formation via increased BMP2 signals. J Bone Miner Res. 2020; 35:1481-1493.

[33] FuKM, Rhagavan P, ShaffreyCI, ChernavvskyDR, SmithJS. Prevalence, severity, and impact of foraminal and canal stenosis among adults with degenerative scoliosis. Neurosurgery. 2011; 69:1181-1187.

[34] PetrosyanE, FaresJ, LesniakMS, Koski TR, El TecleNE. Biological principles of adult degenerative scoliosis. Trends Mol Med. 2023; 29:740-752.

[35] ChenK, ZhaoJ, YangY, et al. Global research trends of adult degenerative scoliosis in this decade (2010–2019): a bibliometric study. Eur Spine J. 2020; 29:2970-2979.

[36] AdamsMA, DolanP, McNallyDS. The internal mechanical functioning of intervertebral discs and articular cartilage, and its relevance to matrix biology. Matrix Biol. 2009; 28:384-389.

[37] WoldtE, SebtiY, SoltLA, et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat Med. 2013; 19:1039-1046.

[38] BoulinguiezA, DuhemC, Mayeuf-LouchartA, et al. NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression. JCI Insight. 2022; 7:e153584.

[39] Chao-yangG, PengC, Hai-hongZ. Roles of NLRP3 inflammasome in intervertebral disc degeneration. Osteoarthr Cartil. 2021; 29:793-801.

[40] SongY, WangY, ZhangY, et al. Advanced glycation end products regulate anabolic and catabolic activities via NLRP3-inflammasome activation in human nucleus pulposus cells. J Cell Mol Med. 2017; 21:1373-1387.

[41] LiaoZ, LuoR, LiG, et al. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics. 2019; 9:4084-4100.

[42] WuN, YinL, HannimanEA, Joshi S, LazarMA. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbα. Genes Dev. 2009; 23:2201-2209.

[43] ChenS, LiuS, ZhaoL, Lin H, MaK, ShaoZ. Heme Oxygenase-1-mediated autophagy protects against oxidative damage in rat nucleus Pulposus-derived mesenchymal stem cells. Oxid Med Cell Longev. 2020; 2020:1-14.

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2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.